Polypeptide hormones exert their actions through receptors, the cellular elements which interact with these hormones with great sensitivity and specificity and, as a consequence of such interactions, modify cellular function. The objective of the research proposed here is to define the chemistry of the interaction between glucagon and its receptor in liver. The glucagon receptor, located in the plasma membrane of the liver cell, is composed in part of an enzyme, adenylate cyclase, whose activity is increased as a result of the action of the hormone on the system. The product of the enzyme, cyclic AMP, mediates the subsequent physiologic effects of the hormone. As a result of previous work, the plasma membrane has been purified from rat liver, and its adenylate cyclase system has been extensively characterized. Binding of glucagon to these membranes has also been studied. The classical enzymologic approach, solubilization, purification, and chemical characterization, appears to be unsuitable for obtaining further information about this receptor system. As an alternative, we plan to use probes of the glucagon receptor. Agents which 1) modify the sensitivity of the system to glucagon but do not alter the catalytic site of adenylate cyclase, 2) alter the affinity of the system for glucagon, or 3) modify any part of the system in a way which can be potentiated or prevented by the substrate, product, cofactors, stimulators, or regulators of adenylate cyclase will be sought. The specificity of these agents will then be established, and, if sufficiently specific, each will be used to obtain chemical information about the system. This research should in the near future have implications for our understanding, diagnosis, and management of diabetes mellitus and other endocrine diseases.